Structure Elucidation and Characterization of Different Thyroxine Polymorphs

Abstract

Thyroid hormones regulate almost every process in the body, including body temperature, growth, and heart rate. They influence carbohydrate metabolism, protein synthesis and breakdown, and cardiovascular, renal, and brain function. Two new polymorphs of synthetic L-thyroxine (T4) are reported and the effect of polymorphism on the solubility of this important hormone is shown. Conformational changes were also discovered to have a remarkable effect on the strength of halogen bonding and the reactivity of the C-I bonds, which could have a significant effect on the hormone activity.

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

“…These conformational differences can influence the physical and pharmacological properties,a nd most importantly,t he reactivity of the C À I bonds of T4. [58] Ac omparison of the conformational parameters,s hown in Figure 4C and Table 1, of free T4 and TBGbound T4 clearly indicates that TBG can alter the conforma- Among all the transport proteins of T4, TBG exhibits an allosteric mechanism for the binding and release of T4. [55,59] TBG switches between two states that have high and low affinities for T4 by using the free movement of the RCL.…”

“…Furthermore,the relative orientation of the amine and carboxylate moieties of T4 also has as ignificant effect on the ability of the iodine atoms to form ah alogen bond with selenium. [58] In af ew conformations,t he 5'-iodine atom can form as tronger halogen bond than the 5-iodine atom, thus indicating that DIO2 may follow asimilar strategy to selectively remove the 5'-iodine atom. However,f urther studies,including the binding mode of T4 at the active site of all three isoforms,are required to validate the hypothesis.…”

Halogen Bonding in Biomimetic Deiodination of Thyroid Hormones and their Metabolites and Dehalogenation of Halogenated Nucleosides

“…Although the tellurium‐containing compounds mediate 5′‐deiodination of THs, DIO1 and DIO2 mediate the same through having selenocysteine in the active site, thus indicating that some other factor might alter the reactivity of the 5‐ and 5′‐iodo substituents. Recently we have shown that commercially obtained T4 exists in at least two different stable conformations with different physical properties . Furthermore, solid‐state 13 C NMR indicated that the reactivities of the C−I bonds in these two conformations are different.…”

Structure Elucidation and Characterization of Different Thyroxine Polymorphs

“…Understanding the effect of conformational change on the reactivity of the C À Ibond is crucial since T4 is apro-hormone and the selective removal of iodine atoms from T4 by three selenoenzymes,t he iodothyronine deiodinases Dio1, Dio2, and Dio3 ( Figure S2 in the Supporting Information), is ak ey step in maintaining its biological activity through receptor binding and thyroid hormone homeostasis. [9] Interestingly,w hen the compound was crystallized from am ixture of acetonitrile and ammonia, relatively larger rhomboid-shaped monoclinic crystals (Form II) in the P2 1 space group were obtained. When we crystallized T4 from amixture of methanol and ammonia, rhomboid-shaped triclinic crystals (Form I) in the P1 space group were obtained ( Figure 2).…”